Bis-basic ethers and thioethers of dibenzothiophene

ABSTRACT

The novel bis-basic ethers and thioethers of dibenzothiophene of the present invention have useful antiviral properties. These new compounds are represented by the formula WHEREIN EACH Y is oxygen or divalent sulfur; and each X is WHEREIN EACH A is a straight or branched alkylene chain having from two to eight carbon atoms and which separates the amino nitrogen and Y by at least two carbon atoms; R and R1 are individually hydrogen, (lower)alkyl having from one to six carbon atoms, cycloalkyl having from three to six carbon atoms, alkenyl having from three to six carbon atoms and having the vinyl unsaturation in other that the 1-position of the alkenyl group; or each set of R and R1 taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, or N(lower)alkylpiperazino; or WHEREIN N IS A WHOLE INTEGER OF FROM 0 TO 2, M IS 1 OR 2, AND R2 is hydrogen, (lower)alkyl having from one to six carbon atoms, or alkenyl of from three to six carbon atoms and having the vinyl unsaturation in other than the 1-position of the alkenyl group. This invention also includes pharmaceutically acceptable acid addition salts of the bases represented by Formula I. These new compounds may be prepared by several different methods which are described.

United States Patent Albrecht et al.

[ 1 June 27, 1972 [54] BlS-BASIC ETHERS AND THIOETHERS OF DIBENZOTHIOPHENE [72] Inventors: William L. Albrecht; Robert W. Fleming; Stephen W. llorgan, all of Cincinnati, Ohio [73] Assignee: Richards-Merrell, lnc., New York, N.Y. 221 Filed: Feb. 18,1970

[21] Appl. No; 12,428

[52] US. Cl. ..260/293.57, 260/3293, 260/3265 SA, 260/246 B, 260/268 TR, 424/267, 424/275, 424/274, 424/248, 424/250 Primary Examiner-Henry R. Jiles Assistant ExaminerS. D. Winters Attorney-Harvey W. Edelblute and George W. Rauchfuss, Jr.

[57] ABSTRACT The novel bis-basic ethers and thioethers of dibenzothiophene of the present invention have useful antiviral properties. These new compounds are represented by the formula s Formula I wherein each Y is oxygen or divalent sulfur; and each X is (A) the group wherein each A is a straight or branched alkylene chain having from two to eight carbon atoms and which separates the amino nitrogen and Y by at least two carbon atoms; R and R are individually hydrogen, (lower)alky1 having from one to six carbon atoms, cycloalkyl having from three to six carbon atoms, alkenyl having from three to six carbon atoms and having the vinyl unsaturation in other that the 1-position of the a1- kenyl group; or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino; or

(B) the group (CH2)n i wherein n is a whole integer of from 0 to 2, m is 1 or 2, and R is hydrogen, (1ower)alkyl having from one to six carbon atoms, or alkenyl of from three to six carbon atoms and having the vinyl unsaturation in other than the 1-position of the alkenyl group.

This invention also includes pharmaceutically acceptable acid addition salts of the bases represented by Formula 1. These new compounds may be prepared by several different methods which are described.

11 Claims, No Drawings BIS-BASIC ETHERS AND 'IHIOE'IHERS OF DIBENZOTHIOPEENE S Formula I wherein each Y is oxygen or divalent sulfur; and each X is A) the group wherein each A is a straight or branched alkylene chain having from two to eight carbon atoms and which separates the amino nitrogen and Y by at least two carbon atoms; R and R are individually hydrogen, (lower) alkyl having from one to six carbon atoms, cycloalkyl of from three to six carbon atoms, alkenyl of three to six carbon atoms and having the vinyl unsaturation in other than the l-position of the alkenyl group; or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, or N-(lower)alkylpipera-zino; or

( B) the group wherein n is a whole integer of from 0 to 2, m is l or 2, and R is hydrogen, (lower) alkyl having from one to six carbon atoms, or alkenyl of from three to six carbon atoms and having the vinyl unsaturation in other than the l-position of the elitenyl group.

The compounds of this invention include both the base form represented by Formula I and pharmaceutically acceptable acid addition salts of the base form.

As can be seen from the above general Formula I, one basic ether or thioether group, that is, YX, is attached to each of the two benzenoid ring of the dibenzothiophene ring system. Thus one of these groups can he linked to the dibenzothiophene ring system by replacement of any one of the hydrogen atoms in positions 1 through 4, while the second of these groups can replace any one of the hydrogen atoms in ositions 6 through 9. Preferably, one of the basic ether or thioether groups is in the 2- or 3- position of the dibenzothiophene ring system, while the remaining group is in the 7- or 8-position, and most preferably one of thex groups is in the 2-position and the other is in the 8-position.

Although one of the two X groups on a compound of the above general Formula I can be and the other can be the group it is preferred that both X groups are the same as more fully shown by the following general Formulas II and III:

Formula II /l\ :pCmH YACHQQE T s (CH2) mNR Formula III In the above general Formulas II and Ill, the various groups Y, A, R, R, R n and m have the same meanings given hereinbefore.

Each of the symbols A in the above Formula ll is an alkylene group having from two to eight carbon atoms which ,can be straight chained, or branched chained, and which separates Y, that is, the ether oxygen or thioether sulfur, from the amino nitrogen by an alkylene chain of at least two carbon atoms. Each of the alkylene groups represented by A can be the same or difierent, although preferably 'both of these groups are the same. Illustrative of alkylene groups represented by A there can be mentioned for example: 1,2- ethylene, 1,3-propylene, 1,4-butylene, l,5-pentylene, 1,6-hexylene, Z-methyl-lA-butylene, 2-ethyl-l,4-butylene, 3-methyll,5-pentylene and the like. Preferably A is an alkylene group having from two to six carbon atoms.

In the compounds of Formula II each amino group, that is,

can be a primary, secondary or tertiary amino group. Each R and R is individually hydrogen, (lower) alkyl having from one to six carbon atoms, cycloalkyl of from three to six carbon atoms, alkenyl of from three to six carbon atoms and having the vinyl unsaturation in other that the l-position of the alkenyl group, or each at of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group. Preterably each of the groups is a tertiary amino group.

Illustrative of (lower)alkyls which can be represented by each R or R in the compounds of Formula ll, or R in the compounds of Formula ill there can be mentioned straight or branched chain alkyls, such as, for example: methyl, ethyl, npropyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, npentyl, isoamyl, n-hexyl and the like.

Hlustrative of cycloallryl goups which can be represented by each R and R in the compounds of Formula II of the present invention there can be mentioned for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

lilush'ative of alkenyl groups which can be represented by R, R, or R of the compounds of the present invention there can be mentioned for example: allyl, 3-butenyl, 4-hexenyl and the like.

The heterocyclic groups which can be represented by each group of Formula II are saturated monocyclic heterocyclic groups. These heterocyclic groups, in addition to the one nitrogen atom, can contain a second hetero atom, such as, for

3,7-bis[ B-(dimethylamino)pr0poxy1dibenzothiophene,

2,8-bis[ 3-( cyclohexylamino )propoxyldibenzothiophene,

2,8-bis[6-(diallylamino)hexoxyldibenzothiophene,

3,7-bis[Z-(pyrrolidino)ethoxyldibenzothiophene,

2,8-bis{2-(N-methyl-N-cyclohexylamino)ethoxyId ibenzothiophene,

2,8-bis[3-(piperidino)propoxy]dibenzothiophene and the like. As examples of base compounds of this invention which are represented by general Formula Ill there can be menexample, oxygen or nitrogen in the ring and four or five ring 10 tioned for example:

carbon atoms. The ring can be substituted with a (lower )-alkyl group, particularly, with an alkyl group having from one to three carbon atoms. As examples of suitable heterocyclic groups which are represented by R and R taken together with the nitrogen atom to which they are attached there can be -bi [2-(N- yl' -p p y yl p mentioned for example, pyrrolidino, piperidino, morpholino, 3 y -PY Y Y) P N-(lower)alkylpiperazino, such as, N-methyl or N-ethyll (N- l y p p fi yl xyl i enmthio hene piperazino and the like. and the likfh Each R, R or R group can be the same or different in each e pha maceutically acceptable acid addition salts of the f h b i ether or hi h groups n h d to h base compounds of this invention are those of any suitable indibenzothiophene ring system. Preferably, however, both of organic or organic acids. Monoor bis-acid addition salts can the R groups, R groups or R groups in each compound are be formed, although in practice, the bis-salts are usually isothe same. Preferred substituents for the R, R and R groups d- A150, the Bells Can be hydrated, for ple, are alkyl radicals having from one to six carbon atoms. monohydrate, or substantially anhydrous. Suitable inorganic Each of the saturated heterocyclic groups of the compounds 2 acids for preparing the salt form are, for example, mineral of Formula Ill can be attached to Y through an alkylene linkacids, such as, hydrochloric, hydrobromic, sulfuric or age of one or two carbon atoms, for example, methylene or phosphoric acids and the like. Suitable organic acids are, for 1,2-ethylene, or each saturated heterocyclic group can be atexample, citric acid, malic acid, glycolic acid, lactic acid, tartached to Y through a ring carbon atom of the heterocyclic taric acid, malonic acid, succinic acid, maleic acid, fumaric group when n is zero. The saturated heterocyclic group is atacid and the like. tached to either the alkylene group or Y through a carbon The compounds of the present invention can be adatom of the ring by replacement of one of the hydrogen atoms ministered to prevent or inhibit infections of: picomaviruses, of the ring. The heterocyclic groups in the compounds for example, encephalomyocarditis; myxoviruscs, for examrepresented by Formula [II can be 5- or 6-membered rings, ple, lnfluenm A PR arboviruses, for example, Semliki that is, m is l or 2. As examples of various groups represented Forest; and poxviruses, for example, Vaccinia IHD. When adb ministered prior to infection, that is, prophylactically, it is preferred that the administration be within 0 to 96 hours prior to infection of the animal with pathogenic virus. When administered therapeutically to inhibit an infection, it is K preferred that the administration be within about a day or two C H2. lafter infection with pathogenic virus.

, The dosage administered will be dependent upon the virus for which treatment or prophylaxis is desired, the type of animal involved, its age, health, weight, extent of infection,

in the compounds of the present invention there can be menkind of concurrent treatment, if any, frequency of treatment, I tioned for example: N-methyl-4-piperidyl, N-methyl-3- and the nature of the effect desired. lllustratively, dosage piperidyl, N-ethyl3-pyn'olidyl, (N-methyl-4- levels of the administered active ingredients can be: inpiperidyDmethyl, (N-methyl-3-piperidyl)methyl, 2-(2- travenously, 0.1 to about 10 mg/kg; intraperitoneal, 0.1 to piperidyl)ethyl and the like. about rug/kg; subcutaneous, 0.1 to about 250 mg/kg;

As examples of base compounds of this invention which are 50 orally, 0.] to about 500 rug/kg and preferably about 1 to 250 represented by general Formula I] there can be mentioned for mglkg, in instillation, 0.1 to about 10 mg/kg; and example: aerosol, 0. l to about 10 rug/kg of animal body weight.

2,8 bis(4-aminobutoxy)dibenzothiophene, The compounds may be administered, dissolved or 2,8-bis[ Z-(diethylaminokthyltlfioldibenzothiophene, suspended, in any conventional non-toxic pharmaceutical car- 3,7-bis[Z-(diethylaminokthoxyldibenzothiophcne, tier of the type that may be taken orally, applied topically, 2,S-bislZ-(diisopropylaminokthoxyldibcnzothiophene, buccally or parenterally. 2,8-bis[S-(di-n-propyIaminoWentoxyldibenmthiophene, The compounds of the present invention may be prepared 2,8-bis[3-(di-n-butylamino)propoxyldibenzothiophcne, by various methods such as, for example, according to the 2,8-bis[3-(dimethylamino )2-methylpropoxy]diben2othio methods described below in the several schemes illustrated by phcne, the equations and in the specific examples.

Scheme 1 H- Y l YH .\'A-Hal. Basic (2 equivs.) l\s/l R *i (1 equivalent) (2 equivalents) a n 1 HaL-A -Hal. 3 I F (l a e z guivs) A Y l I! Y Ax\ R1 /\5/ R 2,8-bis[ 2-( N-methyl-4-piperidyl )ethoxy ldibenzothiophene,

2,8-bis[ 2 N-methyl-4-piperidyl )ethylthio ]dibenzcthiophene,

2,8-bis( N-methyl-4-piperidyloxy )dibenzothiophene,

Formula II (1 equivalent) Formula III (2 e';uivalents) In the above reaction schemes, Y, RRN-, A, R m, and n have the same meanings specified hereinbefore, and each Hal. is Cl, Br or I.

Typical haloalkylamines, 2, useful in Scheme 1 are for example, N,N-diethyl-Z-chloroethylamine, N-(2- chloroethyl)piperidine and the like. Typical dihaloalkanes, 3, useful in Scheme 2 are for example, l-bromo-Z-chloroethane, l,6-dibromohexane and the like. Amines, 5, useful in Scheme 2 are primary amines such as, for example, ethylarnine, or secondary amines, such as, for example, dimethylamine, or tertiary amines, such as, for example, hexarnethylenetetramine and the like. Typical of the halogen substituted heterocyclic nitrogen compounds, 6, useful in Scheme 3 are for example, 3-chloromethyll -methylpiperidine and the like.

In the above reaction schemes, the base used may be for example, sodium methoxide, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide and the like. Solvents used as the reaction medium may vary over a wide range of solvent types and include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated aromatics, such as chlorobenzene and the like; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like; alcohols such as ethanol, isopropanol and the like; ketones such as acetone, butanone and the like; ethers such as tetrahydrofuran, dioxane and the like; water; or mixtures of solvents.

In the method of synthesis where either sodium methoxide, sodium amide or sodium hydride, for example, is used as the base, the reaction is carried out in an anhydrous medium, such as anhydrous toluene, chlorobenzene and the like. About 2.5 equivalents of the base is added to a suspension of, for example, 1 equivalent of compound I where Y is oxygen, in the anhydrous solvent, and the mixture heated to form the diphenoxide. In the case where sodium methoxide is used, the methanol formed may be removed advantageously by azeotropic distillation. About 2.5 equivalents of the halide, 2, 3 or 6, is then added and the mixture heated to reflux for a period which may vary from about 4 to 24 hours. The products, that is, compounds of Formula II or III and compound 4 are then isolated by customary procedures. Compounds of Formula II and III are usually isolated as bis-acid addition salts.

In the method where an alkali hydroxide, such aspotassium hydroxide, for example, is used as the base, two different procedures may be used. In the one procedure a 25 to 50 percent aqueous solution of the alkali hydroxide (about 2.5

- procedure the reaction is carried out in a heterogeneous medium of water and an aromatic hydrocarbon, such as, for example, toluene, xylene and the like. For example, 1 equivalent of compound 1 where Y is oxygen is suspended in the aromatic hydrocarbon. Then in Schemes l and 3, a solution of about 2.5 equivalents of a hydrohalide salt of the amino halide, that is, a hydrohalide salt of 2 or 6, in the minimum volume of water is added and with efficient stirring, a 25 to 50 percent solution of the alkali hydroxide (about 5 equivalents) is added. The mixture is heated to reflux for a period of about 6 to 24 hours, and the product isolated from the hydrocarbon layer. In Scheme 2, when the aqueous/aromatic hydrocarbon medium is used to prepare compounds of type 4, which contain no amine functions, the amount of alkali hydroxide used is only in slight excess of 2.0 equivalents per 1 equivalent of diphenol or dithiol, that is, compound 1 wherein Y is equal to oxygen or divalent sulfur.

In Scheme 2, the reaction between the bis(w-haloalkyl) ether or thioether, 4, and the amine, 5, may be carried out under a variety of conditions. For example, the compound 4 may be heated together with a large excess of the amine, 5, the excess amine serving as both the reaction medium and the hydrohalide acceptor. This method is particularly suitable for readily available amines, the excess of which can be easily removed from the reaction mixture by, for example, distillation at reduced pressure or by steam distillation. Or, 1 equivalent of the bis(m-haloalkyl) ether or thioether, 4, and 4 equivalents of the amine, 5, may be heated together in one of a number of different types of solvents, for example, in aromatic solvents, such as, benzene, toluene, xylene, chlorobenzene and the like; or lower molecular weight alcohols, such as, methanol, ethanol, isopropyl alcohol and the like; or lower molecular weight ketones, such as, acetone, methyl ethyl ketone and the like. The reaction between the halo compound and the amine is usually promoted by the addition of either sodium or potassium iodide, the iodide being used in either catalytic or stoichiometric amounts. In some cases, it maybe advantageous to use only two equivalents of the amine, 5, for and R is not H, or the symmetrically substituted tertiary each equivalent of the bis(w-haloalkyl) ether or thioether, 4, amines, that is, compounds of Formula II wherein R R but an excess of either powdered sodium or potassium carbonate neither is H. being used as the acceptor for the hydrohalide generated. In One method for preparing the secondary amines, that is, the case of volatile amines, this reaction may be best carried compounds of Formula I] wherein R=H and R is not H, is the out under pressure in a suitable bomb-or autoclave. reaction of the primary amines, that is, compounds of Formula ll wherein each R and R is H with the stoichiometric quantischeme 4 ties of the appropriate aldehydes or ketones to yield the cor- 7a R3 R3 73 responding Schitf's bases, which may then be reduced with fl either a borohydride or molecular hydrogen in the presence of 7b 7b (excess) a catalyst, such as platinum or Raney nickel, for example.

S Another method for preparing the secondary amines is acyla- 7 a= tion of the primary amines with the appropriate acyl halides or O R anhydrides, followed by reduction of the N-acyl amines with ll lithium aluminum hydride. 7b R4= C"N Reductive alkylation of the primary amines with an excess R1 of the appropriate aldehydes or ketones in the presence of R R molecular hydrogen and a catalyst, such as platinum or Raney nickel, for example, will yield'the symmetrically substituted tertiary amines, that is, compounds of Formula ll wherein R 1 S 1 R but neither is H. Alkylation of the primary amines with forl maldehyde and formic acid by the Eschweiler-Clarke Formula II (AMA procedure yields the tertiary amines of Formula II in which R In this scheme of synthesis, R, R, A and Y have the same 'lameanings specified hereinbefore, and A is an alkylene chain y the P y ammes f a large Qxcess of having one less methylene, 2 g p in a traight chain appropriate halides yields the symmetrically substituted tertiathan does A, that is, A=A +CH ry amines, that is, compounds of Formula [I wherein R R The intermediate nitriles, 7a, and amides, 7b, may be but is prepared by the method illustrated, for example, in Scheme 1 Alkylation of the secondary amines, that is, compounds of above, in which the appropriate w-haloalkyl nitriles and Formula 11 wherein R H and R is not H by the method illusamides are substituted for the haloalkyl amines, 2, trated in Scheme 5 may be used to prepare either the symmet- According to the method of preparation illustrated in rically substituted tertiary amines, that is, compounds of For- Scheme 4, compounds of Formula II, in which both R and R mula ll wherein R =R but neither is H or the unsymmetrically are hydrogen, may be prepared from either the nitrile 7 o 3 substituted tertiary amines, that is, compounds of Formula II h b it d id 71,, h i R R ]-1 Secondary wherein R and R are different and neither is H.

amines, that is, compounds of Formula II wherein R H and Reaction of the secondary amines with the appropriate ha: -R is not H, can also often be prepared by this method from lides is one method for effecting N-alkylation. Another useful the corresponding secondary amides, 7b, wherein R H and method is the reductive alkylation of the secondary amines R is not H. 40 with the appropriate aldehydes or ketones in the presence of molecular hydrogen and a catalyst, such as platinum or Raney scheme 5 nickel, for example. Another useful alkylation method is the R R two-step method whereby the secondary amines are acylated y fi n with the appropriate acyl halides or anhydrides and the resulting N-acyl amines are reduced with lithium aluminum hydride s to the corresponding tertiary amines. Alkylation of the secon- Formula II (R dary amines with formaldehyde and formic acid by the Another useful method for preparing the bis-basic others and thioethers represented by Formulas II and III is illustrated in Scheme 6.

7 This method is equally applicable to the preparation of bis- In this scheme of synthesis, R, A and Y have the same basic ethers and thioethers represented by Fonnula III, in meanings specified hereinbefore, and with the exceptions which case haloalkylamines of type 6 are substituted for the noted in the two formulas above, R has the same meaning type 2haloalkylamines shown in the above illustration.

Eschweiler-Clarke procedure is a method for preparin the tertiary amines of Formula II in which R CH NAY Y--AN I R Formula II (R is not H) p d her'einbefol'e- By the method of Scheme 6, the bis-basic ethers and Scheme 6 O R ll ll Base CH -C-Y Y-C-CH; NAHal.

(2 equivs.) \s/ R (1 equivalent) (2 equivalents) /N-A-Y Y-AN R s R Formula II Alkylation of the primary amines, that is, compounds of thioethers can be prepared directly from the diacetates of Formula II wherein each R and R is H, by the method illusdibenzothiophene-diols and dithiols, that is, compound 8 trated in Scheme 5 may be used to prepare either the secondawherein Y is equal to oxygen or divalent sulfur, which in some ry amines, that is, compounds of Formula I] wherein R 1-! cases are more conveniently isolated than are the diols and sodium methoxide, sodium ethoxide and the like. Solvents used in this procedure include aromatic hydrocarbons, such as benzene and toluene, and halogenated aromatics, .such as chlorobenzene and the like. Reaction conditions can vary over a wide range with respect to the reaction period and temperature; however, the reaction is generally effected-at the reflux temperature of the solvent for a period of 6 to 72 hours. The preferred method is to heat amixture of compound 8, the hydrochloride salt of compound 2 or 6, and four equivalents of sodium methoxide in refluxing chlorobenzene for 24 hours.

Starting materials which find use in preparing the compounds illustrated in the above reaction schemes and in the specific examples given below are the following dibenzothiophene-diols, that is, compound 1 wherein Y is oxygen: 2,8-dihydroxydibenzothiophene [F .P. Richter and E.W. Fuller (to Socony-Vacuum Oil Co., Inc.), U.S. Pat. No. 2,479,513, Aug. 16, 1949]; and 3,7-dihydroxydibenzothiophene which can be prepared from 3,7- diaminodibenzothiophene [R.l(. Brown, N.A. Nelson and l .C. Wood,-J. Am. Chem. Soc., 74, 1165 (1952)] by conversion to the tetrazonium salt and subsequent hydrolysis of this salt according to either the procedure of Cullinane et al. for converting 2-aminodibenzothiophene to 2-hydroxydibenzothiophene [N.M. Cullinane, C.G. Davies and 6.]. Davies, J. Chem. Soc.

(London), 1435(l936)], or the procedure of Barker and Barker for converting 3,6-diaminofluoren-9-one to 3,6- dihydroxyfluoren-9-one [A. Barker and C.C. Barker, J. Chem. Soc. (London), 870( 1954)]. The corresponding dibenzothiophene-dithiols, that is, compound ,1 wherein Y represents a divalent sulfur atom can be prepared by the thermal rearrangement of the bis-dialkylthiocarbamates of the above described diols, followed by alkaline hydrolysis of the rearranged products, according to the method of Newman and Karnes for the conversion of phenols to thiophenols [M.S. Newman and HA. Karnes, J. Org.Chem., 31, 3980( 1966)].

The diacetates, 8, can be prepared by acetylation of the above described diols and dithiols.

Representative compounds of the present invention and several of the methods of preparing them, mentioned above, are illustrated in the following specific examples:

EXAMPLE 1 2 ,8-BIS( B-PIPERIDINOPROPOXY )DIBENZOTHIOPHE NE DIHYDROCHLORIDE To 200 ml. of water containing 12.0g. (0.3 mole) of sodium hydroxide and 8.5g. (0.039 mole) of 2,8-dihydroxydibenzothiophene were added 200 ml. of toluene and 19.8g. (0.1 mole) of 3-piperidinopropyl chloride hydrochloride, and the heterogeneous reaction mixture was stirred and heated to reflux for 16 hours. After cooling, the organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The free base was chromatographed on alumina, using chloroform as the eluant. After removing the chloroform from the fraction collected, the oily residue was dissolved in ether and treated with ethereal hydrogen chloride to give the desired product which was purified by two recrystallizations from methanol-butanone, m.p. 240242,

H 17 x 233, E a 741.

EXAMPLE 2 2,8-BIS] 2-(DIME'I'HYLAMINO)ETHOXY1D lBENZOTHlOPHENE DlHYDROCHLORlDE To 200 ml. of chlorobenzene was added 16.1 g. (0.0745 mole) of 2,8-dihydroxydibenzothiophene, 16.8g. (0.156

mole) of Z-dimethylaminoethyl chloride and 8.3g. (0.154 mole) of sodium methoxide. The mixture was stirred and heated to reflux for 16 hours. The cooled reaction mixture was filtered and the filtrate was washed with several portions of water, then dried over anhydrous magnesium sulfate. The chlorobenzene solution was evaporated in vacuo. The oily residue was dissolved in ether and treated with ethereal hydrogen chloride to give the desired product which was crystallized from methanol-butanone, m.p. 248250, H O

EXAMPLE3 2,8-BIS[2(DIETHYLAMINO)ETHOXY]D IBENZOTHIOPHENE BIS-DIHYDROGEN CITRATE EXAMPLE 4 2,8-BIS[3 (DIBUTYLAM1NO)PROPOXY]D. IBENZOTHIOPHENE DIHYDROCHLORIDE When the appropriate molar equivalent amount of 3-dibutylaminopropyl chloride was used in place of 3- piperidinopropyl chloride hydrochloride in the procedure described in Example 1, the desired product was obtained after crystallization from chloroform-acetone, l 55l57,

EXAMPLE 5 2,8-BIS[2-(DIISOPROPYLAMINO)ETHOXY] DIBENZOTHIOPHENE DIHYDRQCHLORIDE When the appropriate molar equivalent amount of 2- diisopropylaminoethyl chloride hydrochloride was used in place of 3-piperidinopropyl chloride hydrochloride in the procedure described in Example 1, the desired product was obtained after crystallization from chloroform-acetone, m.p.

EXAMPLE 6 2,8-BIS[3-(DIMETHYLAMINO)-2- METHYLPROPOXY]DIBENZOTHIOPHENE DIHYDROCHLORIDE When the appropriate molar equivalent amount of 3- dimethylamino-Z-methylpropyl chloride hydrochloride was used in place of Z-dimethylaminoethyl chloride in the procedure described in Example 2, and the molar equivalent amount of sodium methoxide was doubled, the desired product was obtained after crystallization from methanol-butanone,m.p. 122: 5 22 233, 808.

EXAMPLE7 2,8-BlS( 2-PIPERIDINOETHOXY)DIBENZOTHIOPHENE DIHYDROCHLORIDE H20 x 233, E 3 753.

max.

11 EXAMPLE 8.

3 ,7-BIS( 3-PIPERIDINOPROPOXY )DIBENZOTHIOPHENE DIHYDROCHLORIDE When 3,7-dihydroxydibenzothiophene substituted for 2,8-dihydroxydibenzothiophene in the procedure described in Example 1, 3,7-bis-( 3-piperidinopropoxy )dibenzothiophene dihydrochloride is obtained.

EXAMPLE 9 2,8-BIS( 3- PIPERIDINOPROPYLTHIO)DIBENZOTHIOPHENE DIHYDROCHLORIDE EXAMPLE 1O 2, 8-BIS[ 2-( Dll-[EXYLAMINO )ETHOXY D IBENZOTHIOPHENE DIHYDROCHLORIDE When the appropriate molar equivalent amount of 2-dihexylaminoethyl chloride hydrochloride is substituted for 3- piperidinopropyl chloride hydrochloride in the procedure described in Example 1, 2,8-bis[2-(dihexyl amino)ethoxy ]dibenzothiophene dihydrochloride is obtained.

EXAMPLE ll 2,8-BIS[2-(ETHYLAMlNO)ETHOXY]DIB EN ZOTHIOPHENE DIHYDROCHLORIDE A. With stirring 80 ml. of percent aqueous sodium hydroxide is added drop-wise, over a period of 30 minutes, to a mixture of 0.1 mole of 2,8-dihydroxydibenzothiophene and 0.3 mole of l-bromo-Z- chloroethane in 400 ml. of water. With continued stirring the mixture is then heated to reflux for 18 hours. When cool, the supernatant water layer is decanted and the residuedissolved in boiling ethanol. The solid which separates on cooling is filtered and recrystallized from ethanol-chloroform to yield 2,8-bis(2-chloroethox y)dibenzothiophene.

B. A mixture of 0.05 mole of 2,8-bis(2-chloroethoxy)dibenzothiophene, 1.0 mole of ethylarnine, 2.0g. of potassiumiodide and 100 ml. of tetrahydrofuran is heated with stirring at 1 10 for 24 hours in a Parr pressure reactor. The solvent and excess amine are removed in vacuo. The residue is treated with dilute sodium hydroxide and extracted with ether. The ether layer is washed twice with water, dried over anhydrous magnesium sulfate and acidified with ethereal hydrogen chloride. The product is crystallized from methanol-ethyl acetate.

EXAMPLE 12 2,8-BIS(2-AMINOETHOXY)DIBENZOTHIOPHENE DIHYDROCHLORIDE By substituting hexamine for ethylamine in the procedure of example 11(8) and using slightly more than two molar EXAMPLE 13 2,8-BIS[6-(DIETHYLAMINO )HEXYLOXY1D IBENZOTHIOPHENE DIHYDROCHLORIDE This compound can be prepared in two steps by the method of Example 1 l. The intermediate 2,8-bis(6-chlorohexyloxy)dibenzothiophene is prepared by substituting the appropriate molar equivalent amount of 6-bromo-1 chlorohexane for 2-bromo'-l-chloroethane in the procedure described in Example 11(A). Reaction of the above intermediate with an excess of diethylamine by the procedure described in Example 1 1(B) gives the desired product.

EXAMPLE 14 2,8-BlS[( l-METHYL-3-PIPERIDYL)METHOXY]DIBE NZOTHIOPHENE DIHYDROCHLORIDE This compound is prepared by substituting the appropriate molar equivalent amount of 3-chloromethyl-1-methylpiperidine for 2-dimethylaminoethyl chloride in the procedure described in Example 2.

What is claimed is:

1. A compound selected from a base of the formula wherein each Y is a member selected from the group consisting of oxygen or divalent sulfur; and each X is the group wherein each A is an alkylene chain having from two to eight carbon atoms and which separates the amino nitrogen and Y by at least two carbon atoms; R and R are individually selected from the group consisting of hydrogen, (lower)alkyl having from one to six carbon atoms, cycloalkyl having from three to six carbon atoms, alkenyl of from three to six carbon atoms and having the vinyl unsaturation in other than the 1- position of the alkenyl group; or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group selected from the group consisting of pyrrolidino, piperidine, morpholino, or N- (lower)alkylpiperazino; or a pharmaceutically acceptable acid addition salt of said base.

2. A compound of claim 1 wherein each Y is oxygen.

3. A compound of claim 2 wherein A is an alkylene chain having from two to six carbon atoms; each R and R is (lower)-alkyl having from one to six carbon atoms or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated mono cyclic heteroc clic group selected from the group consisting of pyrroli mo,

piperidine, or N-(lower)alkylpiperazino and wherein one of the -Y-X groups is in the 2- or 3-position of the dibenzothiophene ring system and the other -Y-X group is in the 7- or 8-position.

4. A compound of the formula (diethylamino)-ethoxy]dibenzothiphene or a pharmaceuti- 5. A compound of claim 4 which is 2,8-bis[2-(dimethyl- 9. A compound of claim 4 which is 2,8-bis[2- amino)ethoxy]dibenzothiophene or a pharmaceutically ac- (diisopropylamino)-eth0xy]dibenzothiophene or a pharceptable acid addition salt thereof. maceutically acceptable acid addition salt thereof.

6. A compound of claim 4 which is 2,8-bis[3-(dibutyl- I amino)propoxy1dibenzothiophene or a pharmaceutically ac- 5 A cflmpounfi Ofclalm 4 hich I 2,8-bl s[2-(pipendmo)- ceptable acid addition salt h f ethoxy1d1laenzothrophene or a pharmaceutically acceptable 7. A compound of claim 4 which is 2,8-bis[3-(dimethylacld addmonsaltthereofamino)-2-methylpropoxy]dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.

8. A compound of claim 4 which is 2,8-bis[2- l0 11. A compound of claim 4 which is 2,8-bis[3- (piperidino)propoxy1dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.

caliy acceptable acid addition salt thereof.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Pmw 10. T 5,675,191

DATED 1 June 27, 1972 T MP-35KB.- Wm. L. Albrecht, Robt. W. F1eming and Stephen W.

Hor an if s certi ed that eno: appears n the fine-identified gated? in-3% sasd Let't-zrs Patent are has-by ccrl'eciec as shown neiow:

On the fi rst page "[75] Ass ignee Richards-Merrel I Inc. should read Richardson-Merrel I Inc. Column 1, I ines 10-15 should read Column 8, I ines 58-65 R N A Hal should read NA-Ha1 R Signed and Scaled this seventh Day of 0ct0|ber1975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN 4119511718 1 1 Commissioner ufParents and Trademarks 

2. A compound of claim 1 wherein each Y is oxygen.
 3. A compound of claim 2 wherein A is an alkylene chain having from two to six carbon atoms; each R and R1 is (lower)-alkyl having from one to six carbon atoms or each set of R and R1 taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group selected from the group consisting of pyrrolidino, piperidino, or N-(lower)alkylpiperazino and wherein one of the -Y-X groups is in the 2- or 3-position of the dibenzothiophene ring system and the other -Y-X group is in the 7- or 8-position.
 4. A compound of the formula wherein each A is an alkylene chain of two to six carbon atoms; each R and R1 is (lower)alkyl having from one to six carbon atoms or each set of R and R1 taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group selected from the group consisting of pyrrolidino, piperidino, or N-(lower)alkylpiperazino, or a pharmaceutically acceptable acid addition salt thereof.
 5. A compound of claim 4 which is 2,8-bis(2-(dimethyl-amino)ethoxy)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.
 6. A compound of claim 4 which is 2,8-bis(3-(dibutyl-amino)propoxy)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.
 7. A compound of claim 4 which is 2,8-bis(3-(dimethyl-amino)-2-methylpropoxy)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.
 8. A compound of claim 4 which is 2,8-bis(2-(diethylamino)-ethoxy)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.
 9. A compound of claim 4 which is 2,8-bis(2-(diisopropylamino)-ethoxy)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.
 10. A compound of claim 4 which is 2,8-bis(2-(piperidino)-ethoxy)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof.
 11. A compound of claim 4 which is 2,8-bis(3-(piperidino)propoxy)dibenzothiophene or a pharmaceuticallY acceptable acid addition salt thereof. 